CN112125805A - Water-soluble magnolol derivative, preparation method of honokiol derivative and intermediate thereof, and related monohydroxy protected intermediate - Google Patents

Water-soluble magnolol derivative, preparation method of honokiol derivative and intermediate thereof, and related monohydroxy protected intermediate Download PDF

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CN112125805A
CN112125805A CN202010955168.3A CN202010955168A CN112125805A CN 112125805 A CN112125805 A CN 112125805A CN 202010955168 A CN202010955168 A CN 202010955168A CN 112125805 A CN112125805 A CN 112125805A
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nitration
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CN112125805B (en
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张平平
刘晔
于国坤
赵强峰
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Beijing Honghui Meditech Co ltd
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Abstract

The invention provides a water-soluble magnolol derivative, a preparation method of the honokiol derivative and an intermediate thereof, and a related monohydroxy protected intermediate. The nitrated intermediate has a structure shown in formula I. Formula I is
Figure DDA0002678355600000011
R2Is hydroxy, and R3Is H; or, R2Is H, and R3Is a hydroxyl group; r1And R4Are each independently selected from C1～C12An electron donating group of (a); the preparation method comprises the following steps: mixing the compound A
Figure DDA0002678355600000012
Carrying out monohydroxy protection with a hydroxyl protection reagent in the presence of an acid binding agent to form a monohydroxy protection compound; wherein R in the compound A1、R2、R3、R4Having the same definition as before, the hydroxy protecting agents are p-toluenesulfonyl chloride and 1-hydroxybenzotriazole; and (3) sequentially carrying out nitration reaction and deprotection reaction on the monohydroxy protected compound to obtain a nitration intermediate. The invention effectively improves the synthesis efficiency of the water-soluble magnolol derivative and the honokiol derivative.

Description

Water-soluble magnolol derivative, preparation method of honokiol derivative and intermediate thereof, and related monohydroxy protected intermediate
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a water-soluble magnolol derivative, a preparation method of the honokiol derivative and an intermediate thereof, and a related monohydroxy protected intermediate.
Background
Magnolol and honokiol are main active ingredients of traditional Chinese medicine magnolia officinalis, and the chemical structural formulas of magnolol and honokiol are respectively as follows:
Figure BDA0002678355590000011
in 1930, magnolol (Chinese herbal medicine; 2005, 36,10, 1591-. Honolizhen et al, China in 1989, also isolated honokiol from Magnolia officinalis (Chinese patent medicine: 1989,11 (8): 223.).
Magnolol and honokiol have wide pharmacological actions such as antibiosis, anti-inflammation, anti-tumor, muscle relaxation, cholesterol reduction and anti-aging (Chinese herbal medicine; 2005, 36,10, 1591-. Later the water solubility of magnolol and honokiol was improved by chemical derivatization, such as the laboratory preparation of magnolol derivatives and honokiol derivatives provided in chinese patent CN 103313264B. However, the preparation method provided in the patent has poor selectivity of the target product in the synthesis step, great difficulty in separating isomers, and difficulty in large-scale production due to the need of column chromatography for multi-step purification.
For the above reasons, there is a need to provide a magnolol derivative and a preparation process of the magnolol derivative, so as to improve the selectivity and simplify the process, and thus, the magnolol derivative is suitable for industrial mass production.
Disclosure of Invention
The invention mainly aims to provide a water-soluble magnolol derivative, a preparation method of the honokiol derivative, an intermediate of the honokiol derivative and a related monohydroxy protected intermediate, and aims to solve the problems that the water-soluble magnolol derivative and the honokiol derivative are low in selectivity and complex in process, and large-scale production cannot be realized in the prior art.
In order to achieve the above objects, according to one aspect of the present invention, there is provided a water-soluble magnolol derivative and a method for preparing a nitration intermediate of the magnolol derivative, wherein the nitration intermediate has a structure represented by formula I:
Figure BDA0002678355590000021
in the formula I, R2Is hydroxy, and R3Is H; or, R2Is H, and R3Is a hydroxyl group; r1And R4Are each independently selected from C1～C12An electron donating group of (a); the preparation method comprises the following steps: mixing the compound A
Figure BDA0002678355590000022
With hydroxy protecting groupsThe agent is subjected to monohydroxy protection in the presence of an acid-binding agent to form a monohydroxy protection compound; wherein R in the compound A1、R2、R3、R4Having the same definition as before, the hydroxy protecting agents are p-toluenesulfonyl chloride and 1-hydroxybenzotriazole; and (3) sequentially carrying out nitration reaction and deprotection reaction on the monohydroxy protected compound to obtain a nitration intermediate.
Further, C1～C12The electron-donating group is selected from C1～C12Alkyl or C1～C12Alkenyl of (a); preferably, C1～C12The electron-donating group of (a) is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, 1-alkenylbutyl, 1-alkenylpentyl or 1-alkenylhexyl; preferably, R1And R4The same is true.
Further, in the monohydroxy protection reaction process, the molar ratio of the compound A to the p-toluenesulfonyl chloride is 1 (0.75-1), and the molar ratio of the compound A to the 1-hydroxybenzotriazole is 1 (0.75-1); preferably, the monohydroxy protection reaction is carried out in a first solvent, which is a non-reactive hydrophobic solvent; preferably, the first solvent is selected from one or more of dichloromethane, chloroform, 1-dichloroethane, methyl tert-butyl ether, toluene; preferably, the molar ratio of the acid-binding agent to the hydroxyl protecting agent is (2-3): 1; preferably, the acid-binding agent is an organic base; more preferably, the organic base is selected from one or more of pyridine, 4-dimethylamino-pyridine, 1, 8-diazabicycloundec-7-ene, triethylamine and N, N-diisopropylethylamine; preferably, the reaction temperature of the monohydroxy protection reaction is-10 ℃ to 25 ℃, more preferably 0 ℃ to 10 ℃, and the reaction time is 6h to 10 h; preferably, in the monohydroxy protection reaction, the molar concentration of compound A is less than 0.2mol/L, more preferably less than 0.1mol/L, relative to the volume of the first solvent.
Further, the step of nitration reaction comprises: reacting a mono-hydroxyl protective compound with nitric acid with the concentration of 60-70 wt% to obtain a nitration product; preferably, the nitration reaction is carried out in a second solvent, the second solvent being a non-reactive solvent; preferably, the second solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, methyl tert-butyl ether, acetic acid; preferably, in the nitration reaction process, adding nitric acid into a second solvent containing a monohydroxy protection compound in a dropwise manner, and reacting at the temperature of 0-25 ℃ to obtain a nitration product; preferably, the weight ratio of the monohydroxy protection compound to the nitric acid is 3.2-4.2: 1 calculated by 65 wt% of nitric acid.
Further, the step of deprotection reaction comprises: mixing the nitration product with a third solvent to form a mixed solution; the third solvent is a non-reactive solvent; preferably, the third solvent is selected from one or more of 1,4-dioxane, n-propanol, ethylene glycol and toluene; an aqueous solution of an alkali metal hydroxide is added to the mixed solution and heated to carry out a reaction, thereby obtaining a nitrated intermediate.
According to another aspect of the present invention, there is provided a method for preparing a water-soluble magnolol derivative and an amino-substituted intermediate of the honokiol derivative, wherein the amino-substituted intermediate has a structure represented by formula II:
Figure BDA0002678355590000031
r in the formula II1、R2、R3、R4Has the same definition as in any one of claims 1 to 5; the preparation method comprises the following steps: preparing a nitrated intermediate shown as a formula I by adopting the preparation method; and carrying out reduction reaction on the nitrified intermediate to obtain the amino substituted intermediate.
Further, the reducing agent adopted in the step of reduction reaction comprises stannous chloride, iron powder and Na2S, NaHS; preferably, the reduction reaction is carried out in a fourth solvent, which is a mixed solvent of alcohol/acid solution, wherein the alcohol is selected from one or more of methanol, ethanol and ethylene glycol, and the acid solution is selected from hydrochloric acid, acetic acid and ammonium chloride aqueous solution; preferably, during the reduction reaction, the reaction system is heated to a reflux state.
According to another aspect of the present invention, there is also provided a method for preparing a water-soluble magnolol derivative and a honokiol derivative free base intermediate, wherein the free base intermediate has a structure represented by formula III:
Figure BDA0002678355590000041
r in formula III1、R2、R3、R4Having the same definition as above, R5Selected from the group consisting of single amino acids or peptides which are free of residues formed by hydroxyl groups during condensation of their carboxyl groups; the preparation method comprises the following steps: preparing an amino substituted intermediate shown as a formula II by adopting the preparation method; carrying out condensation reaction on the amino substituted intermediate and tert-butyloxycarbonyl protected single amino acid or tert-butyloxycarbonyl protected peptide to obtain a condensation product; and (3) reacting the condensation product with hydrogen chloride, alkalifying with ammonia water, extracting and recrystallizing to obtain a free base intermediate.
Further, the single amino acid is selected from one of lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline, glutamic acid, cystine and aspartic acid; the molecular weight of the peptide is less than or equal to 2500 Da; preferably, the molar ratio of the amino substituted intermediate to the tert-butoxycarbonyl protected single amino acid or tert-butoxycarbonyl protected peptide is (1.2-0.8): 1; preferably, the condensation reaction is carried out in a fifth solvent, which is a non-reactive solvent; preferably, the fifth solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran and N, N-dimethylformamide; preferably, in the condensation reaction process, the reaction temperature is 0-30 ℃; preferably, the reaction of the condensation product with hydrogen chloride is carried out in a sixth solvent, which is a non-reactive solvent; preferably, the sixth solvent is selected from one or more of diethyl ether, ethyl acetate, dichloromethane and 1, 4-dioxane.
According to another aspect of the present invention, there is further provided a water-soluble magnolol derivative and a method for preparing the same, wherein the water-soluble magnolol and honokiol derivative have a structure represented by formula iv:
Figure BDA0002678355590000051
r in formula IV1、R2、R3、R4、R5Have the same definitions as in the preceding; x is R5The number of amino groups which can form salts contained in (1); the preparation method comprises the following steps: preparing a free base intermediate represented by formula III by the above preparation method; reacting the free base intermediate with hydrochloric acid, and concentrating or lyophilizing to obtain water-soluble magnolol derivative and honokiol derivative.
According to another aspect of the present invention, there is further provided a water-soluble magnolol derivative and a monohydroxy-protected intermediate of the honokiol derivative, the monohydroxy-protected intermediate having a structure represented by formula V below:
Figure BDA0002678355590000052
wherein, in the formula V, R1And R4Have the same definitions as before; r6Is composed of
Figure BDA0002678355590000053
And R is7Is H; or, R6Is H, and R7Is composed of
Figure BDA0002678355590000054
The invention provides a preparation method of a water-soluble magnolol derivative and a nitration intermediate of the honokiol derivative, which comprises the steps of taking activated ester formed by p-toluenesulfonyl chloride and 1-hydroxybenzotriazole under the action of an acid-binding agent as a hydroxyl protecting reagent, carrying out monohydroxy protection on a compound A, and then sequentially carrying out nitration reaction and deprotection reaction to obtain the nitration intermediate
Figure BDA0002678355590000061
The compound A has a mother nucleus structure of magnolol or honokiol, and two benzene rings of the compound A respectively have hydroxyl groups. The invention uses p-toluenesulfonyl chloride and 1-hydroxybenzotriazole as hydroxyl protecting reagents, and the formed activated ester can realize R in the dihydroxy of magnolol, honokiol and derivatives thereof2And R3The represented hydroxyl is selectively mono-protected, so that the selectivity in the subsequent nitration reaction process is effectively improved, namely the nitration reaction can be carried out at the ortho position of the unprotected hydroxyl. After the nitration reaction is finished, obtaining the nitration intermediate with the structure of the formula I through deprotection reaction. The nitration intermediate is adopted to carry out subsequent reactions such as nitro reduction, tertiary butyloxycarbonyl protected amino acid or peptide condensation reaction, tertiary butyloxycarbonyl protection removal and the like, so that the water-soluble magnolol derivative and the honokiol derivative can be obtained.
In a word, the preparation method provided by the invention effectively improves the selectivity of the nitration reaction of the compound A, and correspondingly improves the synthesis efficiency of the water-soluble magnolol derivative and the honokiol derivative; on one hand, the method is favorable for improving the yield of the target product, on the other hand, the method can completely avoid column chromatography steps, remarkably simplify the synthesis process, reduce the production difficulty and adapt to the requirement of industrial large-scale production.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As described in the background art, the preparation of water-soluble magnolol derivatives and honokiol derivatives in the prior art has problems of low selectivity, complex process and incapability of large-scale production.
In order to solve the problems, the invention provides a water-soluble magnolol derivative and a preparation method of a nitration intermediate of the honokiol derivative, wherein the nitration intermediate has a structure shown in a formula I:
Figure BDA0002678355590000071
in the formula I, R2Is hydroxy, and R3Is H; or, R2Is H, and R3Is a hydroxyl group; r1And R4Are each independently selected from C1～C12An electron donating group of (a); the preparation method comprises the following steps: mixing the compound A
Figure BDA0002678355590000072
Carrying out monohydroxy protection with a hydroxyl protection reagent in the presence of an acid binding agent to form a monohydroxy protection compound; wherein R in the compound A1、R2、R3、R4Having the same definition as before, the hydroxy protecting agents are p-toluenesulfonyl chloride and 1-hydroxybenzotriazole; and (3) sequentially carrying out nitration reaction and deprotection reaction on the monohydroxy protected compound to obtain a nitration intermediate.
The compound A has a mother nucleus structure of magnolol or honokiol, and two benzene rings of the compound A respectively have hydroxyl groups. The invention uses the activated ester formed by p-toluenesulfonyl chloride and 1-hydroxybenzotriazole under the action of an acid-binding agent as a hydroxyl protecting reagent, and the activated ester can realize R in the dihydroxy of magnolol, honokiol and derivatives thereof2And R3The represented hydroxyl is selectively mono-protected, so that the selectivity in the subsequent nitration reaction process is effectively improved, namely the nitration reaction can be carried out at the ortho position of the unprotected hydroxyl. After the nitration reaction is finished, obtaining a nitration intermediate with a structure shown in formula I through deprotection reaction, taking honokiol compound A as an example, the specific reaction route is as follows:
Figure BDA0002678355590000081
the nitration intermediate is adopted to carry out subsequent reactions such as nitro reduction, amino acid condensation reaction protected by tert-butyloxycarbonyl, tert-butyloxycarbonyl removal protection, acid and alkali regulation and the like, and the water-soluble magnolol and the honokiol derivative can be obtained.
It should be noted that the activity of the activated ester formed by p-toluenesulfonyl chloride and 1-hydroxybenzotriazole is relatively lower than that of the direct esterification reaction of toluenesulfonyl chloride, and the steric structure of the activated ester is larger than that of toluenesulfonyl chloride, so that the probability of hydroxyl reaction with larger steric hindrance can be further reduced, and the compound A with magnolol and honokiol dihydroxy structures can be selectively protected by monohydroxy groups due to the above reasons.
In addition, for more sterically hindered protecting agents such as octanoyl chloride and lauroyl chloride, the inventors have found that the hydroxyl position of their selective protection is exactly opposite to the protected position required for compound a above. This shows that the activity of two hydroxyl groups in compound A is high or low (especially for compound A with honokiol mother nucleus structure), the activity of two hydroxyl groups is high or low and is opposite to the steric hindrance, and although the molecular size of octanoyl chloride and lauroyl chloride is larger, the activity difference of the hydroxyl groups in the reaction plays a leading role because of the flexible structure of the fatty chain. In contrast, the activated ester formed by the hydroxyl protecting agent in the present invention is an aromatic ring rigid structure, so that steric hindrance plays a dominant role in the reaction. Based on the researches, the invention obtains the technical scheme of taking the activated ester formed by the p-toluenesulfonyl chloride and the 1-hydroxybenzotriazole as a hydroxyl protective reagent to perform selective monohydroxy protection on the compound A, thereby effectively improving the synthetic selectivity of the whole water-soluble magnolol derivative and the honokiol derivative, reducing the difficulty of purification and separation, simplifying the working procedures and leading the honokiol derivative to be applied in large scale in industrialization.
In addition to this, in the compounds A of the invention, R2Is hydroxy, and R3Is H; or, R2Is H, and R3Is a hydroxyl group; r1And R4Are each independently selected from C1～C12An electron donating group of (a). When R is2Is hydroxy, and R3When is H, a nitrated intermediate of a magnolol derivative is prepared, when R is2Is H, and R3When it is a hydroxyl group, theA nitrated intermediate of the honokiol derivative is prepared. R1And R4Are each independently selected from C1～C12The electron-donating group can further change R in the monohydroxy protection reaction process by utilizing the electron-donating effect of the groups2、R3Selectivity of hydroxyl group at position. In a word, the preparation method provided by the invention effectively improves the selectivity of the nitration reaction of the compound A, and correspondingly improves the synthesis efficiency of the water-soluble magnolol derivative and the honokiol derivative: on one hand, the method is favorable for improving the yield of the target product, on the other hand, the product purification and separation difficulty of each reaction stage is also reduced, the synthesis procedure is obviously simplified, the production difficulty is reduced, and the method can meet the requirement of industrial large-scale production.
To further increase the selectivity of the monohydroxy protection and nitration reaction, in a preferred embodiment, C1～C12The electron-donating group is selected from C1～C12Alkyl or C1～C12Alkenyl of (a); preferably, C1～C12The electron-donating group of (a) is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, 1-alkenylbutyl, 1-alkenylpentyl or 1-alkenylhexyl. More preferably, R is as defined above1And R4The same is true.
In a preferred embodiment, during the monohydroxy protection reaction, the molar ratio of the compound A to the p-toluenesulfonyl chloride is 1 (0.75-1), and the molar ratio of the compound A to the 1-hydroxybenzotriazole is 1 (0.75-1); preferably, the acid-binding agent is an organic base, and the molar ratio of the acid-binding agent to the p-toluenesulfonyl chloride is (2-3): 1; the amount relationship between the raw materials is controlled within the range, which is more beneficial to the monohydroxy protection reaction, thereby further improving the reaction efficiency.
In a preferred embodiment, the monohydroxy protection reaction is carried out in a first solvent, which is a non-reactive hydrophobic solvent, for the purpose of further improving the reaction stability and promoting the reaction to proceed efficiently. In the actual reaction process, p-toluene sulfonyl chloride, 1-hydroxybenzotriazole and an acid-binding agent are added into a first solvent to react to form an activated ester, and then a compound A is added to further react to obtain a monohydroxy protected intermediate compound. More preferably, the reaction temperature is controlled to be 0-25 ℃, and further preferably, the reaction temperature is 0-10 ℃, and the reaction time is 6-10 h. Preferably, the organic base is selected from pyridine, 4-dimethylamino-pyridine, 1, 8-diazabicycloundec-7-ene, triethylamine and N, N-diisopropylethylamine; the first solvent is one or more selected from dichloromethane, chloroform, 1-dichloroethane, methyl tert-butyl ether and toluene. Thus, the reaction selectivity is better, the efficiency is higher, and the reaction stability and the safety are higher.
To further enhance the selectivity and efficiency of the nitration reaction, in a preferred embodiment, the step of nitration reaction comprises: and reacting the mono-hydroxyl protective compound with nitric acid with the mass concentration of 60-70% to obtain a nitration product. Preferably, the nitration reaction is carried out in a non-reactive second solvent, preferably the second solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, methyl tert-butyl ether, acetic acid. When the method is carried out in the solvent, the nitration reaction is more stable and the byproducts are less. Preferably, in the nitration reaction process, adding nitric acid into a second solvent containing a monohydroxy protection compound in a dropwise manner, and reacting at the temperature of 0-25 ℃ to obtain a nitration product; preferably, the weight ratio of the monohydroxy protection compound to nitric acid is 3.7-4.2: 1(65 wt% nitric acid). The nitration reaction is carried out under the reaction conditions and the raw material dosage ratio, so that the method is safer and more stable.
In a preferred embodiment, the step of deprotecting comprises: mixing the nitration product with a third solvent to form a mixed solution; the third solvent is a non-reactive solvent; the third solvent is selected from one or more of 1,4-dioxane, n-propanol, ethylene glycol and toluene; an aqueous solution of an alkali metal hydroxide is added to the mixed solution to carry out a reaction, thereby obtaining a nitrated intermediate.
According to another aspect of the present invention, there is also provided a method for preparing a water-soluble magnolol derivative and an amino-substituted intermediate of the honokiol derivative, wherein the amino-substituted intermediate has a structure represented by formula II:
Figure BDA0002678355590000101
r in the formula II1、R2、R3、R4Have the same definitions as before; the preparation method comprises the following steps: preparing a nitrated intermediate shown as a formula I by adopting the preparation method; and carrying out reduction reaction on the nitrified intermediate to obtain the amino substituted intermediate.
In order to improve the efficiency of the reduction reaction during the actual operation, in a preferred embodiment, the reducing agent used in the step of the reduction reaction comprises stannous chloride, iron powder, Na2S, NaHS; preferably, the reduction reaction is carried out in a fourth solvent, the fourth solvent is a mixed solvent of alcohol/acid solution, wherein the alcohol is selected from one or more of methanol, ethanol and ethylene glycol, and the acid solution is selected from hydrochloric acid, acetic acid and ammonium chloride aqueous solution; preferably, during the reduction reaction, the reaction system is heated to a reflux state.
According to a further aspect of the present invention, there is provided a process for the preparation of a water-soluble magnolol derivative and a honokiol derivative free base intermediate, wherein the free base has the structure shown in formula III:
Figure BDA0002678355590000102
r in the formula III1、R2、R3、R4Having the same definition as before, R5Selected from the group consisting of residues formed by removing hydroxyl groups from a single amino acid or peptide upon condensation of the carboxyl group; the preparation method comprises the following steps: preparing an amino substituted intermediate shown as a formula II by adopting the preparation method; carrying out condensation reaction on the amino substituted intermediate and amino acid protected by tert-butyloxycarbonyl or peptide protected by tert-butyloxycarbonyl to obtain a condensation product; the condensation product reacts with hydrogen chloride, and then the free alkali is obtained by ammonia water alkalization, extraction and recrystallizationAn intermediate.
In a preferred embodiment, the single amino acid is selected from one of lysine, methionine, tryptophan, valine, alanine, glycine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline, glutamic acid, cystine, aspartic acid; the molecular weight of the peptide is less than or equal to 2500D (preferably formed by the amino acids in the types). In order to further improve the reaction efficiency and the yield of the target compound, in a preferred embodiment, the molar ratio of the amino substituted intermediate to the tert-butoxycarbonyl protected amino acid or tert-butoxycarbonyl protected polypeptide is (1.2-0.8): 1; preferably, the condensation reaction is carried out in a fifth solvent selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran, N-dimethylformamide; preferably, in the condensation reaction process, the reaction temperature is 0-30 ℃; preferably, the reaction of the condensation product with hydrogen chloride is carried out in a sixth solvent selected from one or more of diethyl ether, ethyl acetate, dichloromethane, 1, 4-dioxane.
According to another aspect of the present invention, there is provided a water-soluble magnolol derivative and a method for preparing the same, wherein the water-soluble magnolol and honokiol derivative have a structure represented by formula iv:
Figure BDA0002678355590000111
r in formula IV1、R2、R3、R4、R5Have the same definitions as before; x is R5The number of amino groups which can form salts contained in (1); the preparation method comprises the following steps: preparing a free base intermediate having formula III; reacting the free base intermediate with hydrochloric acid to obtain the water-soluble magnolol and honokiol derivatives.
In the actual operation process, the free base intermediate can be acidified by hydrochloric acid and then freeze-dried to obtain the water-soluble magnolol and honokiol derivatives shown in the formula IV. The concentration of hydrochloric acid may be any concentration, and for example, commercially available hydrochloric acid having a concentration of 37% may be used, and dilute hydrochloric acid having a concentration of 1 to 10 wt% is more preferably used.
Based on the fact that the monohydroxy protection reaction and the nitration reaction have high selectivity, the alkali metal deprotection reaction, the condensation reaction, the hydrogen chloride deprotection reaction, the ammonia water alkalization extraction separation, the crystallization purification, the acidification and the freeze-drying which are finally carried out are simple and easy to operate, the preparation of the water-soluble magnolol and the honokiol derivative shown in the formula IV has high conversion rate and yield, and the industrial production is easy to realize.
According to another aspect of the present invention, there is also provided a water-soluble magnolol derivative and a monohydroxy protected intermediate of the honokiol derivative, having a structure represented by the following formula V:
Figure BDA0002678355590000121
wherein, in the formula V, R1And R4Have the same definitions as before; r6Is composed of
Figure BDA0002678355590000122
And R is7Is H; or, R6Is H, and R7Is composed of
Figure BDA0002678355590000123
The monohydroxy protection compound is prepared by the following preparation method: mixing the above compound A
Figure BDA0002678355590000124
Carrying out monohydroxy protection with a hydroxyl protection reagent in the presence of an acid binding agent to form a monohydroxy protection compound; wherein R in the compound A1、R2、R3、R4Having the same definition as before, the hydroxyl protecting agents are p-toluenesulfonyl chloride and 1-hydroxybenzotriazole.
The present application is described in further detail below with reference to specific examples, which should not be construed as limiting the scope of the invention as claimed.
The abbreviations referred to in the examples: DCC: 1, 3-dicyclohexylcarbodiimide; TsCl: p-toluenesulfonyl chloride; HOBT: 1-hydroxybenzotriazole; DIEA: n, N-diisopropylethylamine; SnCl2: stannous chloride; 1, 4-dioxane: 1, 4-dioxane.
Example 1
The following reaction scheme was used to prepare the nitrated intermediate of honokiol derivatives (compound 6)
Figure BDA0002678355590000131
The method comprises the following steps:
preparation of 3,5'-diallyl-2' -hydroxy-4- (4-methylbenzenesulfonic acid) phenol ester-1, 1'-biphenyl (Compound 4) (England name 3,5' -diallyl-2'-hydroxy- [1,1' -biphenyl ] -4-yl 4-methylbenzenesulfonate)
Dichloromethane (160kg) was weighed into a 200L reactor, stirred until the internal temperature decreased to 10 ℃ or less, HOBT (0.744kg) was added, DIEA (1.61kg) was added, TsCl (0.954kg) was added, the reaction was carried out for 30 minutes, and TsCl disappearance was detected by TLC. Weighing honokiol (1.6kg), adding into a reaction kettle, controlling the internal temperature at 5 + -5 deg.C, and continuously stirring for reaction for 6 h. A1N hydrochloric acid solution (20L) was slowly added thereto, and the mixture was stirred for 30 minutes, allowed to stand, and separated. The above acid washing was repeated once. The organic phase was added to a reaction kettle, 1N sodium hydroxide solution (20L) was added, stirred, allowed to stand, separated, and the above alkali washing was repeated once. The organic phase was added to a reaction vessel, and a saturated saline solution (20L) was added thereto, followed by stirring, standing and liquid separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Adding isopropanol (1.91L) into the residue, heating and stirring to dissolve, cooling to precipitate solid, filtering, and concentrating the mother liquor under reduced pressure to obtain yellow oily compound 4(1.28kg), with purity of 87% and yield of 61%
Compound 4: c25H24O4S＝420.14,MS:438[M+NH4]+.1H-NMR(300MHz,CDCl3)9.46(1H,S),7.83-7.81(2H,d),7.52-7.49(2H,d),7.39-7.37(2H,d),7.00-6.97(3H,m),6.85-6.82(1H,m)5,98-5,69(2H,m),5.06-4.96(4H,m),3.34-3.17(4H,m),2.48-2.35(3H,m)
Step two:
preparation of 3,5 '-diallyl-3' -nitro-2 '-hydroxy-4- (4-methylbenzenesulfonic acid) phenol ester-1, 1' -biphenyl (compound 5, british name 3,5'-diallyl-2' -hydroxy-3'-nitro- [1,1' -biphenyl ] -4-yl 4-methylbenzenesulfonate).
Dichloromethane (5L) was weighed into a 10L reaction kettle, stirred, added with compound 4(1.28kg), and cooled to 0 ℃. Concentrated nitric acid (0.304kg) was weighed, added dropwise over 30 minutes, and stirred for 2 hours with TLC detection indicating the reaction was complete. Purified water (2.6L) was added to the reaction solution, and the mixture was stirred for 15min, allowed to stand, and separated. The organic phase was washed with saturated sodium bicarbonate (2.5L) followed by saturated brine (2.5L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Methanol (8L) is added into the residue, the mixture is heated, stirred and dissolved, then the temperature is reduced to 0 ℃, and the yellow solid 863.5g, with the purity of 97 percent and the yield of 61 percent, is obtained after filtration and filter cake drying.
Compound 5: c25H23NO6S2＝465.52，MS：483[M+NH4]+。1H-NMR(400MHz,CDCl3)11.00(1H,s),7.93(1H,d)7.82(2H,d),7.43-7.32(5H,m),7.12(2H,d),5.98-5.75(2H,m),5.16-5.02(4H,m),3.40-3.29(4H,dd),2.47(3H,s)
Step three:
preparation of 3', 5-diallyl-3-nitro-2, 4' -dihydroxy-1, 1'-biphenyl (compound 6, british name 3',5-diallyl-3-nitro- [1,1'-biphenyl ] -2,4' -diol)
1,4-dioxane (5L) and compound 5(0.862kg) were weighed into a 10L reaction kettle and dissolved with stirring. Potassium hydroxide (0.521kg) is weighed and dissolved in water (1.7L) to prepare a mixed solution, the dropwise addition is completed within 20 minutes, and the reaction is completed by TLC detection after 4 hours of reaction at 85 ℃. Cooling, concentrating under reduced pressure, adding dichloromethane (5L) and water (2.5L) into the residue, dropwise adding concentrated hydrochloric acid while stirring until the solution pH is 5, standing, separating, washing the organic phase with saturated sodium bicarbonate (2.5L) and saturated saline (2.5L), drying with sodium sulfate, filtering, concentrating under reduced pressure, adding dichloromethane (1L) into the residue, heating to dissolve, adding n-hexane (8L), stirring at 0 deg.C for 1h, filtering, and drying the filter cake to obtain deep red solid compound 3(0.425kg), with purity of 95% and yield of 74%.
Compound 6: c18H17NO4＝311.33,MS：329[M+NH4]+。1H NMR(400MHz，CDCl3)10.03(1H，s)，7.90(1H，d)，7.35-7.31(2H，m)，6.90(1H，d)，6.11-5.90(2H，m)，5.24-5.11(5H，m)，3.48(2H，d)，3.40(2H，d)
Example 2
The amino-substituted intermediate of honokiol derivatives (compound 7) was prepared using the following reaction scheme
Figure BDA0002678355590000141
Preparation of 3', 5-dipropenyl-3-amino-2, 4' -dihydroxy-1, 1'-biphenyl (compound 7, british name 3',5-diallyl-3-nitro- [1,1'-biphenyl ] -2,4' -diol)
Anhydrous ethanol (2L) was added to a 10L reactor and Compound 6(0.248kg) was added with stirring. Weighing stannous chloride (0.629kg), adding into the reaction kettle, refluxing for 2 hours, and detecting by TLC to finish the reaction. Cooling to room temperature, concentrating under reduced pressure, adding ethyl acetate 5L to the residue, stirring, slowly adding saturated sodium bicarbonate dropwise until the pH becomes 8, a large amount of solid is generated, filtering, separating, collecting the organic phase, washing the filter cake with ethyl acetate 5LX3, combining the organic phases, and concentrating under reduced pressure to obtain a solid compound 7(0.179kg) as a khaki solid with purity of 96% and yield of 80%.
Compound 7: c18H19NO2＝281.14，MS：282[M+H]+，1H NMR(400MHz，DMSO)9.925(1H，s),9.59(1H，s),9.22(1H，s)9.22，7.12(1H，t)，7.06(1H，d)，7.03(1H，d)，5.99-5.86(2H，m)，5.10-4.98(4H，m)，3.32(4H，dd)。
Example 3
The hydrochloride compound of honokiol derivative (compound 10) is prepared by the following reaction scheme
Figure BDA0002678355590000151
The method comprises the following steps:
preparation of 3', 5-dipropenyl-3- [ (S) -2, 6-N-tert-butoxycarbonyl-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1'-biphenyl (Compound 8, England name di-tert-butyl (6- ((3',5-diallyl-2,4'-dihydroxy- [1,1' -biphenyl ] -3-yl) amino) -6-oxohexane-1,5-diyl) (S) -dicarbamate)
Dichloromethane (2.5L), DCC (103.3g) and Boc-L-lys (Boc) -OH (172.3g) were added to a 5L reaction flask in sequence, stirred at 0 ℃ for 30 minutes, then compound 7(139.5g) was added, after completion of the addition, reacted for 2 hours, filtered, and the filtrate was concentrated to give gray foamy solid compound 5(324g) with a purity of 87%
Compound 8: c34H47N3O7＝609.75，MS：610[M+H]+。1H NMR(300MHz，CDCl3)8.637(1H，s)，7.316(5H，s)，6.892(2H，s)，6.099(3H，m)，5.357(1H，s)，5.206(4H，m)，4.670(1H，s)，4.288(1H，m)，3.445(2H，d)，3.314(2H，d)，3.133(2H，t),2.056(2H,m),1.460(22H,m).
Step two:
preparation of 3', 5-dipropenyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1'-biphenyl (Compound 9, England name (S) -2,6-diamino-N- (3', 5-diamyl-2, 4'-dihydroxy- [1,1' -biphenyl ] -3-yl) hexanamide)
The 5L reactor was purged with nitrogen three times, 4.0M hydrogen chloride/ethyl acetate (1.5L) was added, the mixture was stirred and cooled to 0 deg.C, and compound 8(321.1g) was weighed and slowly added to the 3L reactor, and stirred at 0 deg.C for 5 hours, and a solid was formed. TLC detection showed compound 8 to disappear and the reaction was stopped. Adding 1L of 0 ℃ precooled purified water, separating an organic phase, alkalizing an aqueous phase to pH 9 by using ammonia water to generate a solid, extracting the solid by using ethyl acetate 1Lx2, evaporating an extraction liquid to dryness, and crystallizing the residue twice by using a mixed solution of ethyl acetate and n-hexane to obtain a yellow solid compound 10(96.8g, the purity is 98 percent, and the yield in two steps is 48 percent).
Compound 9: c24H31N3O3＝409.53，MS:410。410[M+H]+,1H-NMR(400MHz，MeOH)7.52(1H,d),7.24(2H,m),6.84(2H,t)，6.08(2H,m)，5.11-4.94(4H,m)，3.41(1H,q)，3.39(2H,d)，3.32(2H,d),2.66(2H,t)，1.83(1H,m)，1.66(1H,m)，1.53(4H,m)。
Step three:
preparation of 3', 5-dipropenyl-3- [ (S) -2, 6-diamino-1-hexanoyl ] amino-2, 4' -dihydroxy-1, 1'-biphenyl ∙ dihydrochloride (Compound 10, England name (S) -2,6-diamino-N- (3', 5-diamyl-2, 4'-dihydroxy- [1,1' -biphenyl ] -3-yl) hexanamide
Compound 10(41g) was dissolved in 1M dilute hydrochloric acid (210ml) with stirring at 0 ℃ and lyophilized to give yellowish solid 9(48.2g, 97.8% purity, 100% yield)
Compound 9: c24H33Cl2N3O3＝482.44，MS：410[M+H]+(free state).1H-NMR(400MHz，DMSO)10.43(1H,s),9.46(1H,s),8.61(1H,s)，8.43(3H,s)，7.99(3H,s)，7.33(1H,s)，7.16(2H,t)，6.86(2H,d),5.99(2H,m)，5.09(4H,m)，4.15(1H,d)，3.29(4H,m)，2.77(2H,t),1.89(2H,q),1.63(2H,m),1.47(2H,m)
Example 4
The following reaction scheme was used to prepare the nitration intermediate of magnolol derivatives (compound 13):
Figure BDA0002678355590000161
the method comprises the following steps:
preparation of 5,5'-diallyl-2' -hydroxy-2- (4-methylbenzenesulfonic acid) phenol ester-1, 1'-biphenyl (Compound 11) (England name 5,5' -diallyl-2'-hydroxy- [1,1' -biphenyl ] -2-yl 4-methylbenzenesulfonate)
Methylene chloride (3L) was weighed out and charged into a 5L reaction flask, stirred until the inner temperature became within 10 ℃, HOBT (18.5g) was added, DIEA (40.1g) was further added, TsCl (23.7g) was added, the reaction was carried out for 30 minutes, and TsCl disappearance was detected by TLC. Weighing magnolol (40.0g), adding into a reaction kettle, controlling the internal temperature to be 5 +/-5 ℃, and continuously stirring for reacting for 6 h. A1N hydrochloric acid solution (500mL) was added slowly, and the mixture was stirred for 30 minutes, allowed to stand, and separated. The above acid washing was repeated once. The organic phase was added to a reaction vessel, and 1N sodium hydroxide solution (500ml) was added thereto, followed by stirring, standing, liquid separation, and the above alkali washing was repeated once. The organic phase was added to a reaction vessel, and a saturated saline solution (500ml) was added thereto, followed by stirring and standing for liquid separation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Adding isopropanol (50ml) into the residue, heating and stirring to dissolve, cooling to precipitate solid, filtering, and concentrating the mother liquor under reduced pressure to obtain yellow oily compound 1(33g), with purity of 85% and yield of 57.3%
Compound 11: c25H24O4S＝420.14,MS:438[M+NH4]+.
Step two:
preparation of 5,5 '-diallyl-3' -nitro-2 '-hydroxy-2- (4-methylbenzenesulfonic acid) phenol ester-1, 1' -biphenyl (compound 12, british name 5,5'-diallyl-2' -hydroxy-3'-nitro- [1,1' -biphenyl ] -2-yl 4-methylbenzenesulfonate).
Methylene chloride (120ml) was weighed into a 250ml reaction vessel, stirred, added with compound 11(30.1g) and cooled to 0 ℃. Concentrated nitric acid (7.15g) was weighed, added dropwise over 30 minutes, and stirred for 2 hours, as indicated by TLC detection. Purified water (60ml) was added to the reaction solution, stirred for 15min, allowed to stand, and separated. The organic phase was washed with saturated sodium bicarbonate (60ml) followed by saturated brine (60ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Methanol (8L) is added into the residue, the mixture is heated, stirred and dissolved, then the temperature is reduced to 0 ℃, and the yellow solid compound 12(20.1g) is obtained after filtration and filter cake drying, the purity is 98 percent, and the yield is 60 percent.
Step three:
preparation of 5,5 '-diallyl-3-nitro-2, 2' -dihydroxy-1, 1'-biphenyl (Compound 13, England name 5,5' -diallyl-3-nitro- [1,1'-biphenyl ] -2,2' -diol)
1,4-dioxane (125mL) and compound 12(20g) were weighed into a 250mL reaction flask and dissolved with stirring. Potassium hydroxide (2.8g) is weighed and dissolved in water (50mL) to prepare a mixed solution, the dropwise addition is completed within 20 minutes, and the reaction is completed by TLC detection after 4 hours of reaction at 85 ℃. The reaction mixture was cooled, concentrated under reduced pressure, dichloromethane (250mL) and water (120mL) were added to the residue, concentrated hydrochloric acid was added dropwise with stirring until the PH of the solution became 5, the solution was left to stand, separated, the organic phase was washed with saturated sodium bicarbonate (120mL) and then saturated brine (120mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 13(13g) as a deep red solid with a purity of 97% and a yield of 97%.
Compound 13: c18H17NO4＝311.12，MS：329[M+NH4]+,1H-NMR(300MHz，CDCl3)8.01(1H,d)，7.50(1H，d)，7.18(1H，dd)，7.01(1H，dd)，6.91(1H，dd)，6.04-5.88(2H，m)，5.18-5.06(4H，m)，3.42(4H，dd).
Example 5
Influence of reaction temperature on selection ratio of 3,5'-diallyl-2' -hydroxy-4- (4-methylbenzenesulfonic acid) phenolate-1, 1'-biphenyl (Compound 4) to 3',5-diallyl-4 '-hydroxy-2- (4-methylbenzenesulfonic acid) phenolate-1, 1' -biphenyl 9 (Compound 4a)
Figure BDA0002678355590000181
The method comprises the following steps: 1L of methylene chloride was weighed out and added to a 2L three-necked flask, and the temperature was lowered to-10 ℃ in three separate batches (0 ℃,10 ℃ and 25 ℃), HOBT (12.4g) was added, DIEA (26.9g) was added, TsCl (15.9g) was added, and the reaction was carried out for 30 minutes. Weighing honokiol (26.6g) and adding into a reaction flask, and continuing stirring for reaction for 6 h. Sampling LC-MS detection showed 4: 4a ratio.
The results of the experiment are as follows:
serial number Temperature of Compound 4: 4a ratio
1 -10℃ 14:1
2 0℃ 14:1
3 10℃ 14:1
4 25℃ 10:1
And (4) conclusion: -compound 4 in the range of 10 ℃ to 25 ℃: the ratio of 4a is more than 10:1, and the selectivity is good; the reaction selectivity of the reaction at the temperature of-10 ℃ to 10 ℃ is as high as 14:1, the selectivity is slightly poor at 25 ℃, and the preferable temperature range of 0 ℃ to 10 ℃ is further comprehensively considered, such as the reaction selectivity, equipment and energy conservation.
Example 6
Effect of reactant concentration on the selection ratio of 3,5'-diallyl-2' -hydroxy-4- (4-methylbenzenesulfonic acid) phenolate-1, 1'-biphenyl (Compound 4) to 3',5-diallyl-4 '-hydroxy-2- (4-methylbenzenesulfonic acid) phenolate-1, 1' -biphenyl (Compound 4a)
Figure BDA0002678355590000191
The method comprises the following steps: 1) methylene chloride (500mL) was measured (1L and 2L in two separate batches), the mixture was cooled to 0 ℃ in a 2L three-necked flask, HOBT (12.4g) was added, DIEA (26.9g) was added, TsCl (15.9g) was added, and the reaction was carried out for 30 minutes. Weighing honokiol (26.6g) and adding into a reaction flask, and continuing stirring for reaction for 6 h. Sampling LC-MS detection showed 4: 4a ratio. The results of the experiment are as follows:
serial number Concentration of Compound 4: 4a ratio
1 0.2mol/L(26.6g/500ml) 10:1
2 0.1mol/L(26.6g/1L) 12:1
3 0.05mol/L(26.6g/2L) 15:1
And (4) conclusion: internal compound 4 when the reactant concentration is less than 0.2 mol/L: the ratio of 4a is more than 10:1, and the selectivity is good; further preferred concentrations are less than 0.1 mol/L.
Comparative example 1
The following reaction scheme was used to prepare the nitrated intermediate of honokiol derivatives (compound 3)
Figure BDA0002678355590000192
The method comprises the following steps:
preparation of 3',5-diallyl-4' -hydroxy-2-dodecanoyloxy-1, 1'-biphenyl (Compound 1) (England name 3',5-diallyl-4'-hydroxy- [1,1' -biphenyl ] -2-yl dodecanoate)
Honokiol (5g, 1eq) is weighed and dissolved in ethyl acetate 50ml, pyridine (3.9g,2eq) is added under stirring at 0 ℃, lauroyl chloride (4.5g, 1.1eq) is added dropwise, and stirring is carried out overnight after the addition is finished. The reaction mixture was diluted with 50ml of ethyl acetate, washed with 1N diluted hydrochloric acid, a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography of the crude product (ethyl acetate: petroleum ether ═ 1:20) afforded compound 1(3.6g) in 95% purity and 43% yield
Compound 1: c30H40O3＝448.30,MS:446[M+NH4]+。1H-NMR(300MHz,CDCl3)7.19(4H,m),7.03(1H,d),6.81(1H,d),6.01(2H,m),5.18(4H,m),3.42(4H,m)2.36(2H,t),1.66(2H,m),1.25(16H,m),0.89(3H,t)
Step two:
preparation of 3',5-diallyl-4' -hydroxy-2-dodecanoyloxy-5 '-nitro-1, 1' -biphenyl (Compound 2) (England name 3',5-diallyl-4' -hydroxy-5'-nitro- [1,1' -biphenyl ] -2-yl dodecanoate)
Compound 1(2g, 4.5mmol) was dissolved in 5ml of dried vinegar and stirred at 0 ℃. 0.8ml of concentrated nitric acid is dissolved in 6ml of acetic acid and then is dripped, and the stirring is continued for 1 hour at 0 ℃. The reaction solution was poured into ice water, extracted with ethyl acetate 50ml x2, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 30: 1) to give compound 2(410mg) in 18% yield.
Compound 2: c30H39NO5＝493.28，MS:511[M+NH4]+。
Step three:
preparation of 3',5-diallyl-2,4' -dihydroxy-5 '-nitro-1, 1' -biphenyl (Compound 3) (England name 3',5-diallyl-5' -nitro- [1,1'-biphenyl ] -2,4' -diol)
Compound 2(300mg, 0.6mmol) was dissolved in 5ml of 1,4-dioxane and 5ml of water, NaOH (100mg,2.5mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to acidic pH with 1N diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate: 15: 1) to give the product, compound 3(140mg), 95% pure, 70% yield
Compound 3: c18H17NO4＝311.12,MS:329[M+NH4]+。1H NMR(300MHz，DMSO)10.385(1H，s)，9.579(3H，s)，7.707(1H，s)，7.422(1H，s)，7.200(2H，m)，6.869(1H，s)，5.974(2H，m)，5.062(4H，m)，3.398(4H，m)
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
the process provided by the invention effectively improves the reaction selectivity, has simpler working procedures, still has higher selectivity and yield in the production process of the pilot scale in the embodiment, and has higher synthesis efficiency.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (11)

1. A preparation method of a water-soluble magnolol derivative and a nitration intermediate of the honokiol derivative is characterized in that the nitration intermediate has a structure shown in a formula I:
Figure FDA0002678355580000011
in the formula I, R2Is hydroxy, and R3Is H; or, R2Is H, and R3Is a hydroxyl group; r1And R4Are each independently selected from C1～C12An electron donating group of (a);
the preparation method comprises the following steps:
mixing the compound A
Figure FDA0002678355580000012
Monohydroxy protection is carried out with a hydroxyl protection reagent in the presence of an acid binding agentProtecting to form a monohydroxy protecting compound; wherein R in said compound A1、R2、R3、R4Having the same definition as before, the hydroxy protecting agent is p-toluenesulfonyl chloride and 1-hydroxybenzotriazole;
and (3) sequentially carrying out nitration reaction and deprotection reaction on the monohydroxy protected compound to obtain the nitration intermediate.
2. The method of claim 1, wherein C is the amount of magnolol derivative and the nitration intermediate of magnolol derivative1～C12The electron-donating group is selected from C1～C12Alkyl or C1～C12Alkenyl of (a);
preferably, said C1～C12The electron-donating group of (a) is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, vinyl, allyl, 1-alkenylbutyl, 1-alkenylpentyl or 1-alkenylhexyl;
preferably, R1And R4The same is true.
3. The preparation method of the water-soluble magnolol derivative and the nitration intermediate of the honokiol derivative according to claim 1, wherein during the monohydroxy protection reaction, the molar ratio of the compound A to the p-toluenesulfonyl chloride is 1 (0.75-1), and the molar ratio of the compound A to the 1-hydroxybenzotriazole is 1 (0.75-1);
preferably, the monohydroxy protection reaction is carried out in a first solvent, which is a non-reactive hydrophobic solvent;
preferably, the first solvent is selected from one or more of dichloromethane, chloroform, 1-dichloroethane, methyl tert-butyl ether, and toluene;
preferably, the molar ratio of the acid-binding agent to the hydroxyl protecting agent is (2-3): 1;
preferably, the acid scavenger is an organic base; more preferably, the organic base is selected from one or more of pyridine, 4-dimethylamino-pyridine, 1, 8-diazabicycloundec-7-ene, triethylamine and N, N-diisopropylethylamine;
preferably, the reaction temperature of the monohydroxy protection reaction is-10 ℃ to 25 ℃, more preferably 0 ℃ to 10 ℃, and the reaction time is 6h to 10 h;
preferably, in the monohydroxy protection reaction, the molar concentration of the compound a is less than 0.2mol/L, more preferably less than 0.1mol/L, relative to the volume of the first solvent.
4. The process for the preparation of water-soluble magnolol derivatives and honokiol derivative nitration intermediates according to any one of claims 1 to 3, wherein the nitration reaction step comprises: reacting the monohydroxy protection compound with nitric acid with the concentration of 60-70 wt% to obtain a nitration product;
preferably, the nitration reaction is carried out in a second solvent, which is a non-reactive solvent;
preferably, the second solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, methyl tert-butyl ether, acetic acid;
preferably, in the nitration reaction process, the nitric acid is added into the second solvent containing the monohydroxy protection compound in a dropwise manner, and the reaction is carried out at a temperature of 0-25 ℃ to obtain the nitration product;
preferably, the weight ratio of the monohydroxy protection compound to the nitric acid is 3.2-4.2: 1 calculated by 65 wt% nitric acid.
5. The method of claim 4, wherein the deprotection reaction comprises:
mixing the nitration product with a third solvent to form a mixed solution; the third solvent is a non-reactive solvent; preferably, the third solvent is selected from one or more of 1,4-dioxane, n-propanol, ethylene glycol and toluene;
adding an aqueous solution of an alkali metal hydroxide to the mixed solution and heating to perform a reaction, thereby obtaining the nitrated intermediate.
6. A method for preparing a water-soluble magnolol derivative and an amino-substituted intermediate of the honokiol derivative is characterized in that the amino-substituted intermediate has a structure shown in a formula II:
Figure FDA0002678355580000031
r in the formula II1、R2、R3、R4Has the same definition as in any one of claims 1 to 5;
the preparation method comprises the following steps:
preparing a nitrated intermediate represented by formula I by using the preparation method of any one of claims 1 to 5;
and carrying out reduction reaction on the nitration intermediate to obtain the amino substituted intermediate.
7. The method of claim 6, wherein the reducing agent used in the reduction step comprises stannous chloride, iron powder, Na2S, NaHS;
preferably, the reduction reaction is carried out in a fourth solvent, which is a mixed solvent of alcohol/acid solution, wherein the alcohol is selected from one or more of methanol, ethanol and ethylene glycol, and the acid solution is selected from hydrochloric acid, acetic acid and ammonium chloride aqueous solution;
preferably, during the reduction reaction, the reaction system is heated to a reflux state.
8. A method of preparing a water-soluble magnolol derivative and a honokiol derivative free base intermediate, wherein the free base intermediate has a structure represented by formula III:
Figure FDA0002678355580000041
r in the formula III1、R2、R3、R4Has the same definition as in any one of claims 1 to 5, R5Selected from the group consisting of single amino acids or peptides which are free of residues formed by hydroxyl groups during condensation of their carboxyl groups;
the preparation method comprises the following steps:
preparing an amino-substituted intermediate represented by formula II by the preparation method of claim 6 or 7;
carrying out condensation reaction on the amino substituted intermediate and tert-butyloxycarbonyl protected single amino acid or tert-butyloxycarbonyl protected peptide to obtain a condensation product;
and (3) reacting the condensation product with hydrogen chloride, and then alkalifying, extracting and recrystallizing by ammonia water to obtain the free base intermediate.
9. The method for preparing a water-soluble magnolol derivative and a honokiol derivative free base intermediate according to claim 8, wherein the single amino acid is one selected from lysine, methionine, tryptophan, valine, alanine, phenylalanine, leucine, isoleucine, glycine, histidine, arginine, proline, glutamic acid, cystine, and aspartic acid; the molecular weight of the peptide is less than or equal to 2500 Da;
preferably, the molar ratio of the amino substituted intermediate to the tert-butoxycarbonyl protected single amino acid or tert-butoxycarbonyl protected peptide is (1.2-0.8): 1;
preferably, the condensation reaction is carried out in a fifth solvent, which is a non-reactive solvent; preferably, the fifth solvent is selected from one or more of dichloromethane, 1, 2-dichloroethane, ethyl acetate, tetrahydrofuran and N, N-dimethylformamide;
preferably, in the condensation reaction process, the reaction temperature is 0-30 ℃;
preferably, the reaction of the condensation product with the hydrogen chloride is carried out in a sixth solvent, which is a non-reactive solvent; preferably, the sixth solvent is selected from one or more of diethyl ether, ethyl acetate, dichloromethane and 1, 4-dioxane.
10. A preparation method of water-soluble magnolol derivatives and honokiol derivatives is characterized in that the water-soluble magnolol derivatives and honokiol derivatives have structures shown in a formula IV:
Figure FDA0002678355580000051
r in the formula IV1、R2、R3、R4、R5Has the same definition as in claim 8 or 9; x is R5The number of amino groups which can form salts contained in (1); the preparation method comprises the following steps:
preparing a free base intermediate having formula III by the preparation method of claim 8 or 9;
and reacting the free base intermediate with hydrochloric acid, and concentrating or freeze-drying to obtain the water-soluble magnolol derivative and the honokiol derivative.
11. A water-soluble magnolol derivative and a monohydroxy-protected intermediate of the honokiol derivative, wherein the monohydroxy-protected intermediate has a structure represented by formula V below:
Figure FDA0002678355580000052
wherein, in the formula V, R1And R4Have the same definitions as before; r6Is composed of
Figure FDA0002678355580000061
And R is7Is H; or, R6Is H, and R7Is composed of
Figure FDA0002678355580000062
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114129549A (en) * 2022-02-07 2022-03-04 西北农林科技大学深圳研究院 Application of phenolic compounds in fish disease prevention and control
WO2022052683A1 (en) * 2020-09-11 2022-03-17 北京红惠新医药科技有限公司 Method for preparing water-soluble magnolol derivative and honokiol derivative, methods for preparing intermediates of water-soluble magnolol derivative and honokiol derivative, and related monohydroxy protected intermediate
CN114395076A (en) * 2021-04-19 2022-04-26 北京理工大学 Flame-retardant vinyl ester resin, flame-retardant vinyl ester resin cured product and preparation method
WO2023088062A1 (en) * 2021-11-19 2023-05-25 北京红惠新医药科技有限公司 Anti-hypoxic/anoxic injury use of magnolol and/or honokiol aromatic ring amino-substituted derivative, and pharmaceutical composition

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103113264A (en) * 2013-01-22 2013-05-22 北京红惠新医药科技有限公司 Magnolol derivative, honokiol derivative and preparation method and application thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100892596B1 (en) * 2007-02-12 2009-04-09 바이오스펙트럼 주식회사 Biphenyl Diol Derivatives and Compositions Comprising the Same as an Active Ingredient
EP2423181A1 (en) * 2010-07-28 2012-02-29 Prous Institute For Biomedical Research S.A. Multitarget substituted biphenyl diol derivatives
CN103313264B (en) 2013-06-06 2015-09-02 南京邮电大学 A kind of sensor redundancy node deployment method based on honeycomb grid
CN112125805B (en) * 2020-09-11 2022-10-18 北京红惠新医药科技有限公司 Water-soluble magnolol derivative, preparation method of honokiol derivative and intermediate thereof, and related monohydroxy protected intermediate

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103113264A (en) * 2013-01-22 2013-05-22 北京红惠新医药科技有限公司 Magnolol derivative, honokiol derivative and preparation method and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GEOFFREY WELLS等: "Structural Studies on Bioactive Compounds. 32.1 Oxidation of Tyrphostin Protein Tyrosine Kinase Inhibitors with Hypervalent Iodine Reagents", 《J. MED. CHEM.》 *
ISTVAN F.PELYVAS等: "Regioselective acylation of carbohydrates with 1-acyloxy-1H-benzotriazoles", 《SYNTHESIS》 *

Cited By (6)

* Cited by examiner, † Cited by third party
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WO2022052683A1 (en) * 2020-09-11 2022-03-17 北京红惠新医药科技有限公司 Method for preparing water-soluble magnolol derivative and honokiol derivative, methods for preparing intermediates of water-soluble magnolol derivative and honokiol derivative, and related monohydroxy protected intermediate
CN114395076A (en) * 2021-04-19 2022-04-26 北京理工大学 Flame-retardant vinyl ester resin, flame-retardant vinyl ester resin cured product and preparation method
CN114395076B (en) * 2021-04-19 2022-09-09 北京理工大学 Flame-retardant vinyl ester resin, flame-retardant vinyl ester resin cured product and preparation method
WO2023088062A1 (en) * 2021-11-19 2023-05-25 北京红惠新医药科技有限公司 Anti-hypoxic/anoxic injury use of magnolol and/or honokiol aromatic ring amino-substituted derivative, and pharmaceutical composition
CN114129549A (en) * 2022-02-07 2022-03-04 西北农林科技大学深圳研究院 Application of phenolic compounds in fish disease prevention and control
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